Scientists at the University of Southern California have zeroed in on a specific enzyme linked to Alzheimer's disease and developed compounds that could suppress its harmful activity without crippling healthy brain function.
The enzyme, calcium-dependent phospholipase A2 or cPLA2, appears to drive brain inflammation connected to Alzheimer's risk. The discovery came while researchers studied people carrying the APOE4 gene, the strongest genetic risk factor for the disease. Among APOE4 carriers, those with elevated cPLA2 activity showed higher disease risk.
The challenge was precision: cPLA2 supports normal brain operations, so scientists needed compounds that could dial down its harmful effects while leaving beneficial functions intact. An equally daunting problem was engineering molecules small enough to cross the blood-brain barrier and reach brain tissue effectively.
"In this study, we identified compounds that act selectively on cPLA2, with minimal effects on related PLA2 enzymes that are important for normal cellular function," said Hussein Yassine, director of the Center for Personalized Brain Health at the Keck School of Medicine of USC. "Across cell-based and animal models, cPLA2 activity was reduced at low concentrations, indicating that the compounds are potent in brain-relevant systems."
Computational screening and rapid testing
To find candidates, the team deployed large-scale computational screening across billions of molecules. Researchers prioritized compounds predicted to specifically target cPLA2, penetrate the brain, and maintain activity in biological conditions. Vsevolod Katritch of the USC Dornsife College and the USC Michelson Center for Convergent Bioscience developed the screening methods.
After narrowing the field, pharmacologist Stan Louie of the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences prepared the most promising compounds for animal testing and measured how efficiently they entered brain tissue.
One inhibitor stood out. It reduced harmful cPLA2 activation in human brain cells exposed to Alzheimer's-related stress and successfully crossed the blood-brain barrier in mice. The compound also influenced neuroinflammatory pathways tied to Alzheimer's disease.
Yassine emphasized the next steps remain uncertain. "Our goal is to find out whether targeting inflammation can alter Alzheimer's risk, particularly in APOE4 carriers," he said. "This next phase focuses not on promises, but on carefully determining whether modulating this pathway is safe, feasible, and ultimately meaningful for human disease."
The study, published in the journal npj Drug Discovery, included researchers Anastasiia V. Sadybekov, Marlon Vincent Duro, and Shaowei Wang as co-first authors, along with contributions from Brandon Ebright, Dante Dikeman, Cristelle Hugo, Bilal Ersen Kerman, Qiu-Lan Ma, Antonina L. Nazarova, Arman A. Sadybekov, and Isaac Asante, all affiliated with USC. Three of the researchers, Yassine, Katritch, and Louie, are founders of PeBRx, a company developing cPLA2 inhibitors.
Author Jessica Williams: "This is the kind of targeted approach Alzheimer's research needs, but nobody should expect a cure tomorrow, the human trial phase will be where the real story plays out."
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